Abstract
Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer’s disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu5-positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu5, termed the MPEP (2-Methyl-6-(phenylethynyl)pyridine) binding site. However, one mGlu5 PAM, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu5. Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu5 PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide). NCFP binds to the CPPHA site on mGlu5 and potentiates mGlu5-mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu5 subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu5 in CNS preparations. Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu5 PAMs may have similar responses in some systems, they can induce differential effects on mGlu5-mediated physiologic responses in the CNS. Such stimulus bias by mGlu5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes.
Footnotes
- Received October 10, 2012.
- Accepted January 24, 2013.
This work is supported by the National Institutes of Health National Institute of Mental Health [Grant 2R01 MH062646-13]; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant 2R01NS031373-16A2]; the National Institutes of Health National Institute on Drug Abuse [Grant 1R01DA023947]; Molecular Libraries Probe Production Centers Network [Grants 5 u54 MH84659-03 and 5 u54 MH84659-03S1]; and National Research Service Award from the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant F32 NS071746] (to M.J.N.); NARSAD Young Investigator Award 2011 (to K.J.G.); American Australian Association Merck Foundation Fellowship 2010 (to K.J.G.); and National Health and Medical Research Council (Australia) Overseas Biomedical Postdoctoral Training Fellowship (KJG). The content is solely the responsibility of the authors and does not necessarily represent the official view of the organizations listed above.
This work was previously presented in abstract form: Noetzel MJ, Gregory KJ, Vinson PN, Manka J, Stauffer SR, Xiang Z, Daniels JS, Niswender CM, Lindsley CW, and Conn PJ (2012) Characterization of a potent and efficacious metabotropic glutamate receptor 5 positive allosteric modulator from the CPPHA series, in 2012 Neuroscience Meeting Planner; 2012 Oct 13–17; New Orleans, LA. Society for Neuroscience, Washington, D.C.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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